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SASLT guidelines: Update in treatment of Hepatitis C virus infection

2016; Medknow; Volume: 22; Issue: 8 Linguagem: Inglês

10.4103/1319-3767.188067

1998-4049

AbdullahS Alghamdi, Mohammed Alghamdi, FaisalM Sanai, Hamdan S. Alghamdi, Faisal Abaalkhail, Khalid Alswat, Mohammed A. Babatin, Adel Alqutub, Ibrahim Altraif, Faleh Alfaleh,

Hepatitis B Virus Studies

The Saudi Association for the Study of Liver Diseases and Transplantation (SASLT) formed a task force to evaluate the current methods of optimal management of the Hepatitis C virus (HCV) infection in Saudi Arabia. All members of this committee are hepatologists. The first step was to undertake a broad literature search of the published literature on every aspect of HCV management. All available literature on the topic was critically examined, and the available evidence was then classified according to its importance. The contents of the resulting document, including the recommendations contained in it, have been discussed in detail and agreed upon by the members of the SASLT task force. Subsequently, and after review by the board of directors, the guidelines were approved and endorsed by SASLT. All recommendations in these guidelines are based on the best available evidence, and tailored to patients treated in Saudi Arabia. They are graded on the basis of evidence. The purpose of these guidelines is to improve HCV patient care in the Kingdom and to promote and improve the multidisciplinary care required in the treatment of these patients. They are intended for use by physicians and offer the recommended approaches to treatment of HCV with the new direct-acting antiviral treatment. Grading of recommendations based on quality of evidence Grade A: Recommendation based on at least one high quality randomized controlled trial or at least one high quality meta-analysis of methodologically sound randomized controlled trials. Grade B: Recommendation based on high quality case-control or cohort studies or a high quality systematic review. Grade C: Recommendation based on nonanalytic studies (case reports or case series). Grade D: Recommendation based on expert opinion only. The strength of each recommendation can be divided into: Level 1: strong, based on quality of evidence, patient outcome, and cost Level 2: weak, with variability in values, preferences, and less certainty. Goals of these guidelines These are as follows: To complement the previous SASLT guidelines in the management of hepatitis C in Saudi Arabia To provide an evidence-based approach for the management of HCV-infected patients To eradicate HCV infection. Succeeding in this aim would result in a decrease in liver-related complications, deaths, the need for liver transplantations, and hepatocellular carcinoma rate. INTRODUCTION Hepatitis C virus (HCV) has been reported to be on the decline over the past decade, although it remains a major public health concern in Saudi Arabia. Its prevalence in Saudi Arabia is generally uncertain because most studies were conducted more than 10 years ago. However, data from blood donor screening centers indicates prevalence rates of 0.4–1.1%.[1] The premarital screening data in a predominantly young population from a survey among 74662 individuals conducted in the period between January and May 2008, the results of which were published by the Ministry of Health, showed an HCV prevalence of only 0.33%.[2] Similarly, a community-based study in 16–18 years old Saudi adolescents in 2008 showed a prevalence of HCV at 0.22% in the group.[1] The most prevalent genotype is genotype (GT) 4, followed by GT1. HCV GT4 accounts for 60% of the cases, GT1 for 25.9%, GT2 for 4.3%, GT3 for 2.9%, and GT5/GT6 for 0.3%. 6.3% of the cases were of mixed genotypes, predominantly between GT1 and GT4.[3] The most common subtypes of GT4 are 4a (48%) and 4d (39%), followed by subtypes 4n (6%) and others (6%).[4] Up to 63% of Saudi patients have minimal to moderate (Metavir, F0–2) histological disease.[5] DIAGNOSIS OF HCV Detection of the anti-HCV antibody is the method used for screening of HCV infection. Enzyme immunoassays (EIAs) is the commonly used test, with a specificity of >99% in the detection of anti-HCV.[6] EIA can detect HCV antibodies as early as 6–8 weeks after exposure.[7] Overall, HCV antibody tests have a strong positive predictive value for exposure to the HCV. If anti-HCV antibodies are detected, HCV RNA should then be determined by a sensitive molecular method such as polymerase chain reaction (PCR), transcription mediated amplification (TMA), or branched DNA (b-DNA) with a lower limit of detection of <15 international units (IU)/ml. All HCV nucleic acid molecular tests have the capacity to detect the presence of the virus and to measure the amount of the virus present in the blood (the HCV viral load). Viral RNA testing is also indicated when there is a clinical suspicion of HCV, transaminase levels are high, and antibody testing is negative.[8] HCV genotype and subtype can be determined via various methods, including direct sequence analysis, reverse hybridization, and genotype-specific real-time PCR.[9] Genotyping is useful in epidemiological studies, in selecting therapy, predicting the likelihood of response to the chosen therapy and determining the optimal duration of treatment. Noninvasive laboratory tests to assess liver fibrosis Various noninvasive tests are being investigated for staging the degree of liver fibrosis. These tests may be used to decide whether to initiate or to delay the antiviral therapy and to monitor the effects of such therapy.[10] The use of biochemical markers of liver fibrosis (Fibrotest) and necrosis (ActiTest) can be recommended as an alternative to elastograms and liver biopsy for the assessment of liver injury in patients with chronic hepatitis C. Both have been shown to accurately identify patients with mild fibrosis or cirrhosis. However, they have also been shown to be less effective in discriminating between moderate and severe fibrosis.[11] Transient elastography (Fibroscan) Fibroscan is a technique used to assess liver stiffness without any invasive procedure. The scan can be performed easily, produces no side effects, and is an inexpensive procedure. Fibrosis in the liver can be quantified using elastography. Transient elastography is performed using transducer-induced vibrations at low frequency and amplitudes. Tissue elasticity is detected through pulse-echo ultrasound, which measures shear wave velocity, the S-wave. The wave travels faster in less elastic and stiff livers such as those found in patients with advanced liver fibrosis. Results of liver elasticity are expressed in kilopascals (kPa). A liver stiffness measurement using Fibroscan is reproducible and independent of the operator and explores a volume of liver parenchyma, which can be approximated to a cylinder of 1 cm in diameter and 4 cm in length. This volume is 100 times larger than the biopsy specimen size, and is thus much more representative of the entire hepatic parenchyma.[12] Some extensive studies have demonstrated that the measurement of liver stiffness with Fibroscan is a real alternative to liver biopsy. The amount of fibrosis can be quantified very easily and reliably, and is feasible in more than 95% of the patients. However, the accuracy of the test is hampered by obesity, ascites, and narrow intercostal spaces. Acute hepatitis and liver congestion such as that found in cardiac failure can cause false high scores. Sometimes it may be virtually impossible to take measurements in such patients.[12] Fibroscan values range from 2.4 to 75.5 kPa with cutoff values of 7.1 kPa for F ≥ 2, 9.5 kPa for F ≥ 3 and 12.5 kPa for F = 4 (according to the Metavir histological classification system).[1213] In a study comparing elastography to histological examination on 327 patients, it was concluded that liver stiffness measurements and fibrosis grades were well correlated, with increasing reliability in more extensive fibrosis (F ≥ 3) or cirrhosis. It was impossible to determine a cutoff value to differentiate between F0 and F1 by Fibroscan.[1214] Histology Liver biopsy still remains the gold standard test for evaluating the stages of fibrosis, and, when combined with clinical and laboratory findings, it is also a reliable means of assessing prognosis, thus helping to provide information about the need to initiate therapy. However, biopsy is not mandatory to initiate therapy.[15] Recommendations Diagnosis of HCV infection is based on the detection of anti-HCV antibodies by enzyme immunoassay and HCV RNA by a sensitive molecular method (lower limit of detection ≤ 15 IU/ml), ideally a real-time PCR assay (grade A1) In immunosuppressed patients with undetectable anti-HCV antibodies and in cases of suspected acute hepatitis, HCV RNA test should be a part of initial evaluation (grade A1) Determination of HCV genotype and subtype is recommended and should be used to determine the choice of therapy and duration of treatment (grade A1) Transient elastography can be used to assess liver fibrosis in patients with chronic hepatitis C provided that consideration is given to factors that may adversely affect its performance, such as obesity, age, and biochemical necroinflammatory activity (grade A1) The use of biochemical markers of liver fibrosis (Fibrotest) and necrosis (ActiTest) can be recommended as an alternative to transient elastography and liver biopsy for the assessment of liver injury in patients with chronic hepatitis C (grade A1) Liver biopsy is valuable for assessing the status and level of liver inflammation, the potential progression of fibrosis, and the presence or absence of cirrhosis. It is not mandatory, however, and should be reserved for conditions where there is uncertainty or additional diseases need to be ruled out (grade A1). TREATMENT OF HEPATITIS C VIRUS INFECTION The development of direct-acting antiviral drugs HCV is a small RNA virus consisting of a viral genome—a positive sense, single-stranded RNA—enclosed in a nucleocapsid, or capsid shell, and surrounded by viral envelope E1 and E2, a lipid membrane in which glycoproteins are anchored [Figure 1].[1617] Since the discovery of HCV in 1989,[18] a tremendous amount of research has been undertaken and recorded, which has helped to improve our understanding of HCV virology. Some of the major tools used in this research have included replicon systems—synthetic genetic constructs in which some or all of the HCV genes are allowed to replicate in cell cultures[19]—which have improved the understanding of HCV genomic replication, and retrovirus-based pseudotyped particles,[20] which in turn have improved the understanding of virus entry. The development of a replicon model was a particular turning point in HCV research, considerably expanding the possibilities for studying viral replication and screening potential anti-HCV drugs for activity against viral enzymes. Since 2005, the full HCV lifecycle has also been investigated with the help of complete viral replication systems.[2122] The HCV life cycle involves several steps: (1) host cell attachment, entry, and uncoating; (2) translation of the HCV genome into viral proteins; (3) cleavage and processing of viral proteins; (4) replication of HCV genome; (5) and assembly of new virions and release from host cell.Figure 1: HCV genome organization. The HCV Open Reading Frame encodes three structural proteins, a small protein p7 ion channel, and 6 non-structural (NS) proteins. The structural proteins consist of core (c) proteins and envelop E proteins. The nonstructural proteins consist of NS2, NS3, NS4A, NS4B, NS5A, and NS5B types. Together, NS3/4A, NS4B, NS5A, and NS5B constitute the viral proteins of the replication machinery, which replicates the positive sense RNA genome through a negative strand intermediate. The viral RNA-dependent RNA polymerase NS5B is the key enzyme of RNA synthesisThe treatment of HCV has also progressed over the last 25 years since its discovery. In 1991, the first alfa interferon (IFN-α) was approved for the treatment of hepatitis C. The rates of sustained virologic response (SVR24) were extremely poor, however, and reported to be only 9% for GT1 and 30% for GT2 and GT3. Treatment responses were improved from 1998, with the addition of ribavirin (RBV)[23] (29% SVR for GT1 and 62% for GT2 and 3) and then improved again (to 41–51% SVR for GT1 and 70-82% for GT2 and GT3) in 2001, by linking the IFN (IFN) molecule to polyethylene glycol[24] (PegIFN). Recently, there has been another major breakthrough in hepatitis C treatment with the licensing of the first Direct-Acting Antiviral (DAAs) [Table 1]. These drugs directly target HCV's nonstructural replication machinery proteins (NS3/4A, NS5A, and NS5B), leading to the disruption of HCV replication. The first-generation and first-wave protease inhibitors (PIs) telaprevir and boceprevir were indicated only for GT1 HCV infection, requiring that they be administered in combination with PegIFN-α and RBV as a triple regimen, with estimated SVR results between 65% and 75%.[2526] However, significant drug-adverse events, the complexity of the treatment response-guided regimen, the necessity of PegIFN, the narrow spectrum, and the low genetic barrier of resistance were all major disadvantages associated with the use of these drugs. Moreover, the reported SVR results were far inferior to those of the second-wave DAAs, particularly in difficult to treat populations such as cirrhotics, human immunodeficiency virus (HIV), and organ transplant patients. Consequently, neither drugs are currently indicated for the treatment of HCV infection.Table 1: Currently approved direct-acting drugsThe approval of second-wave DAAs in November and December 2013 set new standards of care for HCV patients. By October 2014, the first INF-free "all-oral regimens" became available, substantially increasing the SVR results to more than 90%. These second-wave DAAs are characteristically associated with favorable drug-safety profiles, shorter treatment durations, superior SVR results, the availability of an INF-free option, and an ability with some regimens to treat HCV in a wide spectrum of conditions, including decompensating cirrhotics, liver transplants, renal, and HIV patients, with excellent results. The currently available DAAs are classified based on the site of the mechanism of action as: NS3-4A PIs that bind to the catalytic site of the enzyme and block post-translational processing of viral polyproteins, preventing the release of functional, nonstructural proteins. First-generation PIs include telaprevir, boceprevir, simeprevir (SMV), ritonavir-boosted paritaprevir (PTV), and asunaprevir, and a second-generation PI is grazoprevir (GZR) NS5A inhibitors that bind to domain 1 of the NS5A protein dimer and block its ability to regulate HCV replication within the replication complex. They also inhibit the assembly and release of viral particles. First-generation NS5A inhibitors include daclatasvir (DCV), ledipasvir (LDV), ombitasvir (OBV), and elbasvir (EBR) Non-nucleoside NS5B polymerase inhibitors that bind to one of four allosteric sites of the RNA-dependent RNA polymerase (RdRp). By altering the conformation of the RdRp, they block its catalytic function, thereby indirectly blocking RNA replication. An example of a non-nucleoside NS5B polymerase inhibitor is dasabuvir (DSV) Nucleotide NS5B polymerase inhibitors that act as false substrates for HCV RdRp, resulting in chain termination after being incorporated into the newly synthesized viral RNA. An example of a nucleotide NS5B polymerase inhibitor is sofosbuvir (SOF). The objectives of hepatitis C virus treatment The primary objective of HCV treatment is to cure hepatitis C infection. An SVR[27] is defined as being when HCV RNA is undetectable 12 weeks (SVR12) after treatment completion, thus indicating cure from infection in more than 99% of patients.[28] The hepatic benefits[29] of getting SVR are considerable, and include histologic regression of necroinflammation and liver fibrosis,[30] as well as reduced risk of complications, such as hepatic failure and portal hypertension. Moreover, the risk of hepatic cell carcinoma (HCC) in cirrhotic patients is reduced, though not eliminated, and all-cause mortality is significantly reduced.[3132] Recommendation The primary objective of treating HCV infected individuals is virological cure as defined by SVR. Elimination of HCV is associated with reduced all-cause mortality and liver related complications (grade A1). Indications and contraindications for hepatitis C virus therapy with direct acting antivirals Indications for therapy DAA treatments of HCV are indicated in all adult patients with active HCV infection, and priority should be given to the following types: Patients with advanced fibrosis (F3) or cirrhosis (F4) including decompensated cirrhosis Patients with HIV or hepatitis B virus (HBV) coinfection All solid organ transplant recipients with HCV RNA positive including patients with recurrence after liver transplantation Patients with extrahepatic HCV-related complications such cryoglobulinemia vasculitis, HCV-related renal disease, or HCV-related malignancy Females of childbearing age who wish to get pregnant Patients discovered to have active HCV at a premarital screening program, irrespective of their disease stage. Contraindications DAA treatments of HCV are contraindicated in: Patients who are less than 18 years old Pregnant or lactating patients or couples unwilling to comply with adequate contraceptive measures HCV patients with a life expectancy ≤1 years Patients with hypersensitivity to any component of the formulation Potential major drug–drug interaction between the DAA HCV medication and another vital medication that cannot be changed or stopped by the patient for any reason Patients with Child Pugh B/C cirrhosis should not receive SMV, PTV/OBV and/or DSV or EBR/GZR as HCV therapy Patients with severe renal impairment (CrCl < 30 mL/min) or patients on hemodialysis should avoid sofosbuvir-based therapy. DRUG–DRUG INTERACTION WITH DIRECT-ACTING ANTIVIRALS With the revolution in HCV treatment and the development of strong and efficacious drugs comes the concern of drug safety and drug–drug interactions (DDI). Learning about drug interactions through experience of using DAA will help to avoid drug-related toxicities. Of great concern are the patients infected at a later age because most of these have other comorbid illnesses such as hypertension, diabetes, heart failure, dyslipidemia, or those co-infected with HIV and on antiretroviral drugs. The issue is also important in patients taking immunosuppressive drugs after organ transplants or for inflammatory diseases. Three mechanisms need to be understood in order to simplify the mechanism of DDI. The first mechanism operates in the blood stream and with protein binding. Displacement of the drug binding to protein can initiate over or underexposure to the active drug. The second mechanism is related to and comes out of cell transportation. Affection of these proteins, polypeptides (1B1 and 1B3) and P-glycoprotein (P-gp), related to influx (drug penetration within cell) and efflux (elimination out of the cell), respectively, are part of drug interaction. The third mechanism is related to liver metabolism itself and drug clearance that affects cytochrome P450 and glucuronidation. This is the most common route for influencing drug metabolism, leading to abnormal drug exposure. One of the most helpful initiatives has been the creation of a website for DDI, which has been led by the University of Liverpool. Queries on drug interactions can be rapidly solved on this website (www.hep-druginteractions.org). Moreover, it is updated on a regular basis, as new information becomes available, and hence can be considered reliable. HCV protease inhibitor SMV and PTV are of the new PI class of DAAs. SMV has a long half-life, and is extensively bound to plasma proteins (>99.9%), primarily to albumin. Elimination occurs via biliary excretion whereas renal excretion is negligible. SMV moderately inhibits CYP3A4 and P-gp in the gut and OATO1B1 in the hepatocyte.[33] Therefore, SMV should not be prescribed with HIV PIs and neither with HIV non-nucleoside analog inhibitors. Tenofovir, emtricitabine, lamivudine, and abacavir have no interactions with SMV, and can thus safely be used in patients receiving this drug. In individuals with impaired liver function, SMV elimination is reduced owing to its primary elimination by the liver, and exposure to SMV increases from 2.4 to 5.2-folds. A number of compounds are contraindicated in patients receiving SMV, including anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), antibiotics (erythromycin, clarithromycin, telithromycin), antimycobacterials (rifampin, rifabutin, rifapentine), systemically administered antifungals (itraconazole, ketoconazole, posaconazole, fluconazole, voriconazole), and systemically administered dexamethasone and cisapride. Dose adjustments are needed with some antiarrhythmics, warfarin, calcium channel blockers, HMG Co-A reductase inhibitors, and sedative/anxiolytics. No dose changes are required when used in combination with the immunosuppressants tacrolimus and sirolimus; however, monitoring of blood concentrations of the tacrolimus and sirolimus is recommended. In contrast, use of cyclosporine has been shown to result in significantly increased plasma concentrations of SMV (due to hepatic uptake transporter inhibition) such that it is not recommended to coadminister the drugs. PTV is boosted with ritonavir and both inhibitors of CYP3A4. High exposure to medications that are metabolized by this complex is a major concern.[34] Drug interactions need to be carefully considered in the setting of coinfection with HIV. A number of drugs are contraindicated because elevated plasma exposure would lead to serious adverse events, among which are alfuzosin, amiodarone, astemizole, terfenadine, cisapride, ergot derivatives, lovastatin, simvastatin, atorvastatin, oral midazolam, triazolam, quetiapine, quinidine, salmeterol, and enzyme inducers that might compromise virological efficacy, e.g., carbamazepine, phenytoin, phenobarbital, rifampicin, St John's wort, enzalutamide, and enzyme inhibitors that might increase PTV exposure, e.g., azole antifungals, and some macrolide antibiotics. Tenofovir reduces PTV exposure by 32%. Conversely, tenofovir increases PTV by 24%. GZR is an HCV NS3/4A PI and a substrate of OATP1B1/3 transporters. The related drug interactions of GZR/EBR combination have been mentioned in the EBR section. Hepatitis C virus polymerase inhibitors Hepatitis C virus NS5B polymerase inhibitors SOF is nucleos (t) ide analog. It requires phosphorylation in the liver to be active as a chain terminator of the nascent HCV RNA chains within the infected hepatocytes. The major form circulating in the blood is the inactive metabolite GS-331007, which is eliminated by the kidney. Thus, SOF exposure increases in patients with renal impairment and dose adjustments should be considered.[35] In cirrhotic patients, SOF exposure increases by 130%. SOF is transported by P-gp and any potent drugs. P-gp inducers significantly decrease SOF plasma concentrations and may lead to a reduced therapeutic effect. Thus, SOF should not be administered with other known inducers of P-gp such as rifampin, carbamazepine, and phenytoin. There are potential interactions that may occur with rifabutin, rifpentine, and modafinil. SOF coadministration with tenofovir along with HIV PIs is discouraged as increased tenofovir disoproxil fumarate exposure enhances the risk of tubulopathy and necessitates periodic checking of glucosuria, phosphaturia, and proteinuria. No significant DDI have been reported with HIV medications. Administration of amiodarone with SOF is contraindicated because of a serious risk of symptomatic bradycardia. DSV is a non-nucleoside polymerase inhibitor. It is mainly biliary excreted. DSV does not exert inhibitory or inducing effects on CYP450, and therefore, no significant major drug interactions are expected.[36] Hepatitis C virus NS5A polymerase inhibitors DCV, LDV, and OBV are of this group with a lower barrier to resistance, with frequent selection of mutations at amino acid residues A30, L31, and Y93. DCV is absorbed in the intestine and bioavailability is reduced by 23% with a fatty meal. Elimination of DCV is mainly fecal (88%) with a small amount excreted in urine.[37] In contrast, DCV exposure diminishes in patients with hepatic insufficiency, most likely as result of hypoalbuminemia, although the free concentration of the drug does not change much; therefore, no dose adjustment is recommended. DCV is a substrate for CYP3A4 and P-gp, and inhibits transporters organic anion transporting polypeptides 1/3 as well as P-gp. This further explains why HIV PIs boosted with ritonavir increase DCV exposure by two fold. Therefore, the daily dose of DCV must be reduced to half (30 mg/day) when coadministered. DCV slightly increases cyclosporine or tacrolimus exposure. On the other hand, cyclosporine increases DCV concentrations by 40%. LDV is administered with SOF. It exhibits very low potential for drug interactions with lower potency.[38] LDV is mainly excreted in bile and transported by P-gp and breast cancer resistant protein (BCRP). LDV needs to be monitored closely when used with the statin group. Rosuvastatin is also not recommended. The concentration and solubility of LDV decreases with high pH, therefore, proton pump inhibitors (PPI), antacids, and H2-receptor antagonists are likely to decrease concentrations of LDV. Both H2-receptor antagonists and PPI need to be administered simultaneously or 12 h apart. Currently, no safety and efficacy data on the combination of SOF and LDV administered along with boosted HIV protease containing regimens have been reported upon. OBV is a substrate of CYP3A4 and P-gp, and inhibits CYP2C8 and UGT1A1. In patients with moderate-to-severe hepatic insufficiency, OBV exposure increases by up to 55%. It contributes to hyperbilirubinemia when taken with other UGT1A1 substrates.[39] EBR is combined with GZR, an HCV NS3/4A PI, and both are substrates of CYP3A and P-gp; however, the role of intestinal P-gp in the absorption of EBR and GZR appears to be minimal. EBR/GZR are contraindicated in strong CYP3A inducers (phenytoin, carbamazepine, rifampicin, HIV medications such as atazanavir, darunavir, lopinavir, saquinavir, tipranavir) or inhbitiors (cyclosporine) efavirenz. EBR/GZR are not recommended with moderate CYP3A inducers (as nafcillin, some HIV drugs, modafinil,) or inhibitors (elvitegravir, cobicistat) because these either decrease or increase the plasma concentration of both drugs, respectively. No dose adjustments are needed when EBR/GZR are used with the following drugs individually: acid reducing agents (proton pump inhibitors, H2 blockers, antacids), buprenorphine/naloxone, digoxin, dolutegravir, methadone, mycophenolate mofetil, oral contraceptive pills, phosphate binders, pitavastatin, pravastatin, prednisone, raltegravir, RBV, rilpivirine, tenofovir disoproxil fumarate, and SOF. No clinically relevant DDI is expected when EBR/GZR are co-administered with abacavir, emtricitabine, entecavir, and lamivudine.[40] Monitoring during IFN-free regimens Clinical assessment during treatment with an IFN-free regimen focuses on adherence to the regimen and the emergence of adverse effects. Monitoring viral levels during treatment with IFN-free regimens has minimal prognostic value because almost all patients without cirrhosis in large clinical trials of IFN-free regimens achieve an undetectable HCV viral level after 4 weeks of treatment.[41] An additional reason to check viral levels during therapy is to assess adherence to the regimen. Given the expense of the medications and the potential risk of viral resistance with inappropriate use, HCV RNA quantitative testing at week 4 in clinical practice and also rechecking HCV RNA quantitative testing at week 6 if the week 4 level is detectable, and discontinuing therapy if the level has increased by >1 log is recommended. The clinical value of a week 12 (or end of treatment) viral level is uncertain, and most providers do not routinely check it. It is undetectable in a vast majority of treated patients, even among those who have subsequent viral relapse. In one study, all 6 patients with quantifiable but low level (<65 IU/mL) viremia at the end of DAA-based treatment had achieved an SVR. Follow-up after treatment Virological response to treatment should be assessed by checking the viral load at 12 to 24 weeks following the cessation of therapy. SVR is defined by an undetectable viral level at this point. An undetectable level at week 12 after treatment is generally maintained until week 24. However, a small proportion of patients (approximately 2%) experience virological relapse between weeks 12 and 24.[4243] Patients who achieve an SVR and do not have bridging fibrosis or cirrhosis do not require any specific follow-up for their HCV, even though some physicians will check an HCV viral load 1 year after the completion of treatment to confirm that the patient has achieved an SVR. On the other hand, those patients who fail to achieve an SVR should be followed for signs of progression of their liver disease. Patients with bridging fibrosis and cirrhosis, regardless of whether they attain an SVR, warrant ongoing monitoring because they continue to be at a risk of hepatocellular carcinoma or other complications of advanced liver disease, which require ongoing surveillance. Treatment of hepatitis C virus genotype 1 Treatment of HCV GT1 used to be a challenge, with the least acceptable chance of SVR among other genotypes. However, with the recent advances in direct acting antivirals, the SVR rate for these patients has increased dramatically.[444546] The choice of therapy here depends on factors such as efficacy, duration, adverse side effects, previous exposure to therapy, type of previous response, and degree of fibrosis.[4445] DAA-based regimens result in higher SVR rates for GT1